Guanidines

ABSTRACT

Novel substituted phenylguanidine compounds and processes for their preparation are disclosed. Their use as anti-hypertensive agents is also revealed.

United States Patent Douglas et al.

[451 Oct. 21, 1975 GUANIDINES Inventors: George H. Douglas, Paoli; Julius Diamond, Lafayette Hill, both of Pa.

Assignee: William H. Rorer, Inc., Fort Washington, Pa.

Filed: July 13,1973

Appl. N0; 379,085

Related US. Application Data Continuation-impart of Ser. No. 291,474, Sept. 22, 1972, abandoned.

US. Cl. 260/562 R; 260/295.5 S; 260/404.5; 260/465 E; 260/50l.l4; 260/558 R; 260/558 S; 260/565; 424/266; 424/312; 424/316; 424/324; 424/326 OTHER PUBLICATIONS Chemical Abstracts, Vol. 64 Column 19833(h).

Primary Examiner-Gerald A. Schwartz Attorney, Agent, or Firm-James A. Nicholson [57] ABSTRACT Novel substituted phenylguanidine compounds and processes for their preparation are disclosed, Their use as anti-hypertensive agents is also revealed.

8 Claims, No Drawings GUANIDlNES CROSS REFERENCE TO RELATED APPLICATIONS SUMMARY OF THE INVENTION ment of hypertensive disorders by the administration of a substituted phenylguanidine compound is also described.

BACKGROUND OF THE INVENTION The pharmaceutical compositions which have been used as antihypertensive agents have included such as the thiazides, reserpine, hydralazine, a-methyl dopa, guanethidine and the like. These compounds, however, while being effective produce undesirable side effects such as electrolyte inbalance, orthostatic hypertension, and gastric secretory and spasmolytic properties.

We have unexpectedly found that guanidine compounds exhibit valuable pharmocologic properties.

We have unexpectedly found that the guanidines of this invention are useful antihypertensive agents.

We have also unexpectedly found that guanidines of this invention are also useful intermediates for the preparation of amidinourea compounds which are useful antihypertensive agents.

We have further found that the guanidine compounds of this invention are novel and can easily be prepared.

We have also found that the compounds of this invention'have a minimum of the side effects which accompany antihypertensive agents.

We have still further found a simple and effective method for the treatment of cardiovascular disorders such as hypertensive disorders;

DESCRIPTION AND PREFERRED EMBODIMENT This invention describes a class of novel chemical compounds which comprises a substituted phenyl radical which is further attached to a guanidine chain. This invention also describes the non-toxic pharmaceuti cally acceptable salts and the method of preparing these substituted phenylguanidine compounds.

The novel compounds of this invention are described by the structural formula I where:

described by general formula I X is hydrogen or halo;

Y is hydrogen, halo. haloloweralkyl, nitro, loweralkyl or loweralko'xy;

Z is haloloweralkyl, haloloweralkoxy or loweralkylsulfo nyl;

Z is also halo, loweralkoxy, loweralkyl, nitro or cyano provided X and Y are not both hydrogen at the same time; 1

R is hydrogen or loweralkyl;

R, R" and R'" are hydrogen, loweralkyl, intermediate alkyl, loweralkenyl, cycloalkyl, cycloalkylloweralkyl, aryl, aralkyl, cycloalkenyl, acyl or aroyl;

R" and R" together are loweralkylidenyl or heteroloweralkylidenyl;

and the non-toxic acid addition salts thereof.

Compounds of this invention which are preferred are where: V

X is hydrogen or halo;

Y is hydrogen, halo, loweralkyl or haloloweralkyl; and

Z is halo or loweralkyl, provided X and Y are not both hydrogen, or haloloweralkyl;

R is hydrogen or loweralkyl; and

R, R" and R'" are hydrogen, loweralkyl, cycloalkyl, acyl or aroyl.

The more preferred compounds of this invention include those compounds where:'

X is hydrogen, chloro, bromo or fluoro;

Y is hydrogen, chloro, bromo, fluoro, methyl or trifluoromethyl;

Z is chloro provided X and Y are not both hydrogen, bromo provided X and Y are not both hydrogen, fluoro provided X and Y are not both hydrogen, methyl provided X and Y are not both hydrogen, trifluoromethyl;

R is hydrogen or methyl; 1

R is hydrogen;

R" is hydrogen, methyl, ethyl, propyl, i-propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acetyl, propionyl or benzoyl; and

R' is hydrogen, methyl, ethyl, acetyl or propionyl.

The most preferred compounds of this invention are described where:

X is hydrogen, chloro, bromo or fluoro;

Y ishydrogen, chloro, bromo, fluoro, methyl or trifluoromethyl;

Z is chloro provided X and Y are not both hydrogen, bromo provided X and Y are not both hydrogen, fluoro provided X and are not both hydrogen, methyl provided X and Y are not both hydrogen, or trifluoromethyl;

R is hydrogen or methyl;

R is hydrogen;

R" is hydrogen, methyl, ethyl, propyl, i-propyl, butyl, acetyl or propionyl; and R'" is hydrogen or acetyl.

A special embodiment of this invention is described where X is hydrogen. Y is 2-chloro and Z is 6-chloro.

Another special embodiment is described where X and Y are hydrogen and Z is 4-fluoro.

A further special embodiment is described where R', R" and R" are hydrogen, acetyl or propionyl.

In the descriptive portions of this invention, the following definitions apply:

The term loweralkyl refers to an alkyl hydrocarbon group containing from 1 to 5 carbon atoms which may be straight chained or branched.

The term intermediate alkyl" refers to an alkyl hydrocarbon group containing from 610 l 2.carbon atoms which may be straight chained or branched.

The acyl" radical may be any organic radical derived from an organic acid by its removal of the hydroxyl group such as acetyl, propionyl, etc.

The. aroyl" radical may be any aromatic organic radical derived from an organic acid by its removal'of the hydroxyl group such as benzoyl, toluyl; etc.

The loweralkoxy' radical signifies an alkoxy group containing from 1 to-about 6 carbon atoms which can be straight chained or branched The,low eralkenyl" group refer to an alkenyl hydrocarbon group containing from 2 .to about 6 carbon atoms which may be straight chained or branched.

"Cycloalkyl refers toa cycloalkyl hydrocarbon ring having from 3 to 8 carbon atoms.,

Cycloalkenyl refers to a cycloallgenyl hydrocarbon ring having from 3 to 8 carbon atoms.

The loweralkylidenyli radical refers to an alkylidene hydrocarbon radical containing from 2 to 8 carbon atoms thus forming ,a ring.- I

The heteroloweralkylidenyl radical refers to an alkylidene hydrocarbon radical containing from 2 to 8 carbon atoms and one or. more hetero atoms selected from oxygen, nitrogen and surfur, thus forming a hetero ring. 1

Aryl" refers to an aromatic'ring preferably phenyl.

This invention further describes a new method for the treatmentof cardiovascular disorders'by the administration of a therapeutically effective amount of a guanidine compound of formula II where:

R R R R and R may be the same or different and are hydrogen, provided at least one of R- R R R and R is other than hydrogen, halo, haloloweralkyl, nitro, cyano, loweralkylsulfonyl, loweralkoxy or loweralkyl; g

R, R, R and R are hydroge'n, loweralkyl, intermediate alkyl loweralkenyl, cycloalkyl, cycloalkylloweralkyl, aralkyl,cycloalkenyl, acyl, aroyl or aryl;

R and R together are loweralkylidenyl or heteroloweralkylidenyl; and I the non-toxic acid additionsalts thereof.

The preferred compounds which are useful in the treatment of cardiovascular disorders are eitemplified by those compounds of formula III i where:

X, Y and Z' may be the same or different and are hydrogen, provided at least one of X, Y and Z is *4 other than hydrogen,'*'halot haloloweralkyl, nitro, cyano, loweralkylsulfonyl, loweralkoxy or loweralkyl;

R is hydrogen or loweralkyli and I R, R" and R are hydrogen, loweralkyl, cycloalkyl, 5 acyloraroyl. m

The'more preferred compounds which are useful in the treatment of cardiovascular disorders are shown in formula Ill where:

X, Y and Z are hydrogen, provided at least one of X; Y" and Z is other than hydrogen, halo, haloloweralk'yl or-low eralkyl;

R is hydrogen or methyl;

R is hydrogen;

i R" is hydrogen, methyl, ethyl,'propyl, i-p'ropyl, butyl, cyclopropyl, ttyclobutyl,cyclopentyl, cyclohexyl, acetyl; propionyl-or'benzoyl;'and i U V --R" is hydrogen, methyl, ethyl, acetyl or propionyl.

The most preferred compounds are described by formula lll wheres.

X is hydrogen, chloro", bromo or fluoro;

Y ishyd roge'n, chloro, bromo, fluoro, methyl or tri- Z is 'chlor'o, bromo," fluoro, methyl or, trifluorom'eth'yh V i I R is hydrogen'or methyl; v

R is hydrogen, methyl, ethyl, propyl, i-propyl, butyl,

acetyl orpr opionylj and R is hydrogen or ae'etyll I A special embodiment of'this" invention isidescribed where X is hydrogem-Y is 2-chl'oro and Z is 6-chloro. Another special embodiment is described where X and Y are hydrogen and Z is 4-chloro. A further special embodiment of this invention is described where R, R and R are hydrogen and R is hydrogen, acetyl or' p'ropionyl. It is well known in the pharmacological arts that nontoxic acid addition salts of pharmacologically active amine compounds do not differ in activities from their free base. The salts" merely provide, a convenient solubility factor. f

The amines of this inventio nrnay be readily converted to their non-toxic acid addition salts by customary methods in the art. The non-toxic salts of this invention are'those salts vtheacid cornponentof which is pharmacologically acceptable in the intended dosages, 'i.e., salts of-pharmaceutically acceptable acids; such 50 salts would include those prepared from inorganic acids, organic acids, higher fatty acids high'molecular weig ht acids, etc., and include such as:

succinic acid, glycolic acid, lactic acid, salicylic acid, bcnzoic acid, nicotinie acid. phthalic acid, stearic acid, oleic acid. abietic acid, etc.

hydrochloric acid, hydrobromic acid; sulfuric acid,

nitric acid. phosphoric acid, methane sulfonic acid. bcnzcnc sulfonic acid. acetic acid,

propionic acid.

malic acid,

, 5, 2,5-dichlorophenylguanidine 2,6-dichlorophenylguanidine 3,4'dichlorophenylguanidine 3,5-dichlorophenylguanidine 2,3,4-trichlorophenylguanidine 2,3,5-trichlorophenylguanidine 2,3,6-trichlorophenylguanidin'e 2,4,S-trichloropheylguanidine 2,4,6-trichlorophenylguanidine 3,4,5-trichlorophenylguanidine o-bromophenylguanidine m-bromophenylguanidine p-bromophenylguanidine 2,3-dibromophenylguanidine 2,4-dibromophenylguanidine 2,5-dibromophenylguanidine 2,6-dibromophenylguanidine 3,4-dibromophenylguanidine 3,5-dibromophenylguanidine 2-chloro-3-bromophenylguanidine 2 chloro-4-bromophenylguanidine 2-chloro-5-bromophenylguanidine 2-chloro 6-bromophenylguanidine 3-chloro-2-bromophenylguanidine 3-chloro-4-bromophenylguanidine, 3-chloro-5-bromophenylguanidine 3-chloro-o-bromophenylguanidine 4-chloro-2-bromophenylguanidine 4-chloro-3-bromophenylguanidine 2-fluoro-4-chlorophenylguanidine 2-fluoro-6-chlorophenylguanidine 2-chloro-4-fluorophenylguanidine Z-fluoro-6-bromophenylguanidine 2-bromo-4-fluorophenylguanidine 2-iodo-4-chlorophenylguanidine Y 2'iodo-6-chlorophenylguanidine 2-chloro-4-iodophenylguanidine 2-iodo-4-bromophenylguanidine o-fluorophenylguanidine m-fluorophenylguanidine p-fluorophenylguanidine p-iodophenylguanidine 2,4-difluorophenylguanidine 2,5-difluorophenylguanidine 2,o-difluorophenylguanidine 2,4-diiodophenylguanidine 2-iodo-6bromophenylguanidine 2-bromo-4-iodophenylguanidine 2-fluoro-4-iodophenylguanidine 2-iodo-4-fluorophenylguanidine 2,4-dichloro-6bromophenylguanidine 2,6-dichloro-4-bromophenylguanidine 2,4-dibromo-6-chlorophenylguanidine 2.6-dibromo-4-chlorophenylguanidine 2,4-dichloro-6-fluorophenylguanidine 2,6-dichloro-4-fluorophenylguanidine 2,5-dichloro-4-fluorophenylguanidine 2,4-dichloro-6-iodophenylguanidine 2,6-dichloro-4-iodophenylguanidine 2,4-dibromo-6-iodophenylguanidine' 2,4-dibromo-6-fluorophenylguanidine 2,6-dibromo-4-fluorophenylguanidine 2-chloro-4-bromo-6-fluorophenylguanicline 2-bromo-4fluoro6-chlorophenylguanidine 2-bromo-4-chloro-6-fluorophenylguanidine 2-chloro-4-iodo-6-bromophenylguanidine 2,4,6-trifluorophenylguanidine I o-trifluorome'thylphenylguanidine m-trifluorornthylphenylguanidine 6 p-trifluoromethylphenylguanidine p-trifluoromethoxyphenylguanidine p-methylsulfonylphenylguanidine 2-chloro-4-nitrophenylguanidine 2-bromo-4-nitrophenylguanidine 2-iodo-4-nitrophenylguanidine 2-fluoro-4-nitrophenylguanidine 2-nitro-4-chlorophenylguanidine 2-nitro-4- bromophenylguanidine 2-nitro-4-fluorophenylguanidine 2-nitro-4-trifluoromethylphenylguanidine 2-nitro-4-methoxyphenylguanidine 2-cyano-4-chlorophenylguanidine 2-chloro-4-cyanophenylguanidine 2-methyl-4-chlorophenylguanidine Z-methyl-4-bromophenylguanidine 2-methyl-4-fluorophenylguanidine 2-methyl-4-nitrophenylguanidine 2 methyl-4-c yanophenylguanidine 2-methyl-4-trifluoromethylphenylguanidine 2,4-dimethylphenylguanidine 2,6-dimethylphenylguanidine 2,6-dimethyl-4-chlorophenylguanidine 2,6-dimethylA-fluorophenylguanidine 2,o-dimethyl-4-bromophenylguanidine 2,6-dimethyl-4-nitrophenylguanidine 2,6-dimethyl-4-trifluoromthylphenylguanidine 2-chloro-4-methylphenylguanidine 2-br0mo-4-methylphenylguanidine 2-fluoro-4-methylphenylguanidine 2-nitro-4-methylphenylguanidine 2,6-dichloro-4-methylphenylguanidine 2,4-dichloro-6-nitrophenylguanidine 2,6-dichloro-4-nitrophenylguanidine 2-ethyl-4-nitrophenylguanidine 2-ethyl-4-chlorophenylguanidine 2-ethyl-4-brom0phenylguanidine 2-ethyl-4-fluorophenylguanidine 2-ethyl-4-trifluorophenylguanidine 2-cyano4-methylphenylguanidine 2-trifluoromethyl-4-methylphenylguanidine 2-trifluoromethyl-o-chlorophenylguanidine 4-trifluoromethyl-Z-chlorophenylguanidine 4-trifluoromethyl-2-bromophenylguanidine 4-trifluoromethyl-2-fluorophenylguanidine 2,4-dichloro-6-methylphenylguanidine 2,6-dichloro-6-rnethylphenylguanidine 3 ,5-ditrifluorom'ethylphenylguanidine 2,5-difluoromethyl-4-nitrophenylguanidine 2-methoxy-4-nitrophenylguanidine 2,4-dichloro-6-methoxyphenylguanidine The compounds of this invention exert activity on the cardiovascular system. They possess blood-pressure lowering effects and are useful as antihypertensive agents. v

For these purposes, the guanidines of this invention can be normally administered orally or parenterally. Orally they may be administered as tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, preserving agents and the like, in order to provide a pharmaceutically elegant and I palatable preparation.

The dosage regimen in carrying out the methods of this invention is that which insures maximum therapeutic response until improvement is obtained and thereafter the minimum effective level which gives relief.

Thus, in general, the dosages are those that are therapeutically effective in the alleviation of hypertensive disorders. In general, the daily dose can be between about 0.05 mg/kg/day and 70 mg/kg/day (preferably in the range of 1-25 mg/kg/day), bearing in mind, of course, that in selecting the appropriate dosage in any specific case, consideration must be given to the patients weight, general health, age, and other factors which may influence response to the drug.

Various tests in animals have been carried out to show the ability of the compounds of this invention to exhibit reactions that can be correlated with activity in humans.

One such test is the ability of the compound to lower blood pressure in the spontaneous hypertensive rat (Ryo Tab'ei, et al., Clin. Pharm. & Therap. 11: 269-274, 1970). Blood pressure measurements arerecorded by both the tail cuff method and by direct cannulation of a common carotid artery. Compounds that are effective antihypertensives in man have been shown to be active in lowering blood pressure in this animal model. In view of the results of this test, the guanidines of this invention can be considered to be active antihypertensive agents.

The compounds of this invention are also useful as intermediates for the preparation of pharmaceutically active agents. Thus, for example, the compounds of this invention may be used to prepare those pharmaceutically active amidinourea compounds disclosed in copending application U.S. Ser. No. 291,474 described above.

The compounds of this invention may be prepared by the following general synthesis:

Condensation of cyanamide and a substituted aniline results in the corresponding substituted phenylguanidine.

The reaction is preferably carried out on the aniline salt either in a polar medium or neat and using increased temperatures. The salt used may be any acid addition amine saltbut preferably the salt of a mineral acid. The polar medium may be aqueous, partially aqueous or a non-aqueous solution. It is convenient tochoose a solvent that will reflux at the desired reaction temperture. The more preferred solvents are water or alcohol but other solvents may be used such as DMSO, diethyleneglycol, ethyleneglycol, tetrahydrofuran, dimethylformamide, etc. The most preferred solvent is a mildly acidic solvent which is non-nucleophilic such as phenol, cresol, xylenol, etc. The reaction should also be carried out at a temperature which is high enough so that condensation takes place readily, but not sufficient to decompose the guanidine formed. The reaction temperature can vary from room temperature to about 250C although it is preferable to run the reaction at temperatures from about 50C to 150C. The guanidine salt which is formed can be converted to the free base with a metal hydroxide or alkoxide solution. The isolation of the desired guanidine can be carried out by any method known in the art.

When R substitution is desired, it is convenient to dichloroaniline would result in dichlorophenyl l -methylg'uanidine.

the 1-(2,6 -f.

The following reaction equations illustrate this synthesis:

HX' is a mineral acid.

When R and/or R" substitution is desired, it is convenient to carry out the condensation using the appropriately substituted cyanamide. Thus, for example, ethyl or diethylcyanamide condensed with 2,6- dichloroaniline would result in the corresponding 1- (2,6-dichlorophenyl)-3-diethylguanidine.

Condensation of an aniline with benzoyl thiourea re sults in the l-substitutedphenyl-3-benzoylthiourea.

This may then be hydrolyzed to the l-substitutedphenylthiourea and treated with iodomethane to obtain the l-substitutedphenyl 2 methylpseudothiouronium iodide. When the latter is treated with an amine of the Condensation may also take place between an aniline formula NHR'R", the resultant displacement yields the and a substituted pseudothiourea under the above reacl-substitutedphenyl-3-RR" guanidine. tion conditions NFLSCN COCl- CONCS x x Y Y fl CONCS NH, NHCNHCO Y H Y 3 s i H q) 10% mon can 1 Q9 9 NH- NHCO NH-C=NH,|

Y f"= Y When the above benzoyl group is replaced by any 40 X R' group condensation with the desired aniline results Y in a l-substitutedphenyl-3-R" thiourea. Treatment N'R"' with iodomethane ives the l-substituted hen 1-2- W methyl-3-R' pseudo thiouronium iodide. Rep iaceriient MC SC N with an amine of the formula NHR'R" results in the l- 45 substitutedphenyl-2-R'"-3-R', R" guanidine.

z Z CH3! These compounds may also be prepared by reacting the desired aniline with an R. R" substituted thiocyanate to form the thioguanidine. This is then reacted with a loweralkyl iodide to form the thiouronium salt and condensation with an amine ofthe formula NHR"--- results in the desired guanidine. 4 I 1 Treatment of a l-substitutedphenylguanidine with an anhydride affords the diacylguanidine. Selective hydrolysis with acid yields the l-substitutedphenyl-3-acyl guanidine.

Appropriately desired end products having various X, Y and Z substituents may be prepared at various steps of synthesis using suitable reactions in order to convert one group to another.

The starting anilines are either known, may be prepared by known techniques or reference to the preparation is shown. Thus, chlorination or bromination of an acetanilide or aniline may be carried out in acetic acid, or in the presence ofa small amount of iodine dissolved in an inert solvent such as carbon tetrachloride. A solution of chlorine or bromine is then added while the temperature is held near C. lodination may also be carried out by known methods using iodine monochloride (Cl l). v

Alkylation may be carried out on an acetanilide using an alkyl halide and aluminum chloride under Friedel- Crafts conditions to obtain desired alkyl substitution.

Nitration may be carried out using fuming nitric acid at about 0C.

-A nitro compoundmay be hydrogenated to the cor- V responding amine whichmay then bediazotized and may be alkylated to the alkylthio group which is .then

:5 "oxidized to the corresponding alkylsulfonyl substituent.

- A halo compound in which halo is chloro or bromo or iodo may be reacted withcuprous cyanide in guanidine at about 150C to produce a cyano compound.

A chloro, bromo or iodo compound may also be reacted with trifluoromethyliodide and copper powder at about 150C in dimethylformamide to obtain-a trifluoromethyl compound. [Tetrahedron Letters: y4 7 4095 1959) j '2 A halo compound rnay also be reacted witlicuprous methanesulfinate in qiiinoline at about 150C to obtain a methylsulfonyl compound. 1

Of course, the above reactions may also be carried out on acetophenone in order to direct substitution. Formation of an oxime followed by Beckmann Rearrairgcmcnt results in the acetamide which; is then deacylated to the aniline. Reactions may also be carried out on the-substituted 'anilihes' which would result in dian trisubstituted'anilines, l

Reactions may also be carried out at other stages of synthesis depending on the substituents present and the substituents desired and various combinations of the foregoing'reactions will be determined by one skille'd in the art in order that the desired product results. Thus, a phenyl'guanidine may/be halogenated or nitrated as above, etc."

The-following are detailed examples which show the p'reparationof the compounds of this'invention'. They' are to be construed as illu'stratiohs of said compounds and not as limitations thereof.

EXAMPLE 1 2,6-Dichlorophenylguanidine I 'To "51 g ((1315 mole) of 2,6-dichloroaniline is added 0.4 mole of ethereal HCl and 200 ml of m-cresol. The

mixture is then stirred and heated on a steam bath to with hexane and theprecipitate is filtered off and wash,ed' with ether and dried to obtain 2,6- dichlorophenylguanidine hydrochloride. .'The free base is prepared by dissolving :dichlorophenylguanidine hydrochloride in 10% sodium TABLE I 2-nitro-6-methoxyaniline 2-cyano-6-chloroaniline 2-methyl-6-chloroaniline 2-methyl-6-bromoaniline 2-methyl-6-fluoroaniline 2-r'nethyl-6-nitroariiline 2-methyl-6-trlfluoromethylaniline Z-methyl-G-cyanoaniline 2-methyl-6-methylsulfonylaniline 2,4-dimethylaniline 2,6-dimethylanilinc Z-trifluoromethyl-fi-chloroaniline Z-trifluoromethyl-6-bromoaniline 24rifluoromethyl-G-fluoroaniline v 2-trifluoromcthyl-6-nitroaniline Z-trifluoromethyl-4-chloroaniline 2-trifluoromethyl-4-bromoaniline Z-trifluoromethyl-4-fluoroaniline 4-trifluoromethyl-Zchloroaniline 4-trifluoromethyl-Z-bromoaniline 4-trifluoromethyl-Z-fluoroaniline 2,4-dichloro-6-methylaniline 2,6-dichloro-4-methylaniline 3.5-ditritluoromethylaniline 2-methoxy-4-nitroaniline 2-trifluoromethyl-4-nitroaniline 2,4-dichloro-fi-methoxyaniline 2,6-dimethyl-4-chloroaniline 2,6-dimethyl-4-fluoroaniline 2,6-dimethyl-4-bromoaniline 2.6-dimethyl-4-nitroaniline 2.6-dimethyl-4-trifluoromethylaniline 2-ethyl-4-nitroaniline 2-ethyl-4-chloroaniline 2-ethyl-4-bromoaniline 2-ethyl-4-fluoroaniline 2-ethyl-4-trifluoromethylaniline 2-ethyl-4-cyanoaniline 2-ethyl-4-methylsulfonylaniline 2,4-dichloro-6-bromoaniline 2.6-dichloro-4-bromoaniline 2,4-dibrom0-6-chloroaniline 2,6-dibromo-4-chloroaniline 2,4-dichloro-6-fluoroaniline 2,6-dichloro-4-fluoroaniline 2,5 dichloro-4-fluoroaniline 2.4-dichloro-6-iodoaniline 2,6-dichloro-4-iodoaniline 2,4-dibromo--iodoaniline 2.4-dibromo-fi-fluoroaniline 2.6-dibromo-4-fluoroaniline 2-chloro-4-bromo-6-fluoroaniline 2-bromo-4-fluoro-6-chloroaniline 2-bromo-4-chloro-fi-fluoroaniline 2-chloro-4-iodo-6-bromoaniline 2,4.6-tribromoaniline 2,4.6-trifluoroaniline TABLE ll Continued 2-nitro-6-methoxyphenylguanidine 2-cyan0-6-chlorophenylguanidine 2-methyl-6-chloroph'enylguanidine 2-methyl-6-bromophenylguanidine 2-methyl-6 fluorophenylguanidine 2-methyl-6-nitrophenylguanidine 2-methyl-6-trifluor0methylphenylguanidine 2-rnethyl-6-cyanophenylguanidine 2-methyl-6-methylsulfonylphenylguanidine I2,4-dimethylphenylguanidine 2,6-dimethylphenylguanidine 2-trifluoromethyl-6-chlorophenylguanidine 2-trifluoromethyl-6-bromophenylguanidine Z-trifluoromethyl-fi-fluorophenylguanidine 2-trifluoromethyl-6-nitrophenylguanidine 2-trifluoromethyl-4-chlorophenylguanidine 2-trifluoromethyl-4-bromophenylguanidine 2-trifluoromethyl-4-fluorophenylguanidine 4-trifluoromethyl-Z-chlorophenylguanidine 4'-trifluoromethyI-Z-bromophenylguanidine v 4-trifluoromethyl-2-bromophenylguanidine 2,4-dichloro-fi-methylphenylguanidine 2,6-dichloro-4-methylphenylguanidine 3,5-ditrifluoromethylphenylguanidine 2-methoxy-4-nitrophenylguanidine 2-trifluoromethyl-4-nitrophenylguanidine 2,4-dichloro-6-methoxyphenylguanidine Z,6-dimethyl-4-chlorophenylguahidine 2,6-dimethyl-4-fluorophenylguanidine 2,6-dimethyl-4-bromophenylguanidine 2,6-dimethyl-4-nitrophenylguanidine 2.6-dimethyl-4-trifluoromethylphenylguanidine I 2-ethyl-4-nitrophenylguanidine 2-ethyl-4-chlorophenylguanidine 2-ethyl-4-bromophenylguanidine 2-ethyl-4-fluorophenylguanidine 2-ethyl-4-trifluoromethylphenylguanidine 2-ethyl-4-cyanophenylguanidine 2-ethyl-4-methylsulfonylphenylguanidine 2,4-dichloro-o-bromophenylguanidine 2,6-dichloro-4-bromophenylguanidine 2,4-dibromo-fi-chlorophenylguanidine 2,6-dibromo-4-chlorophenylguanidine 2,4-dichloro-6-fluorophenylguanidine 2,6-dichloro-4-fluorophhenylguanidine 2,S-dichlorophenylguanidine 2,4-dichloro-6-iodophenylguani dine 2,6-dichloro-4-iodophenylguanidine 2,4-dibromo-6-iodophenylguanidine 2,4-dibromo-6-fluorophenylguanidine 2,6-dibromo-4-fluorophenylguanidine 2,chloro-4-bromo-6-fluorophenylguanidine 2-bromo-4-fluoro-G-chlorophenylguanidine Z-bromo-4-chloro-6-fluorophenylguanidine 2-chloro-4-iodo-6-bromophenylguanidine 2,4,6-tribromophenylguanidine 2,4,6-trifluorophenylguanidine EXAMPLE 2' l-( 2,6-Dichlorophenyl l -methylguanidine filtered oft and washed with ether and dried to obtain l-(2 ,6-dichlorophenyl l -methylguanidine hydrochloride.

cooled, added to 150 ml of conc. sodium hydroxide so:

lution, cooled and extracted with 2 liters of ether. The

ether layer is washed with 2 X 1 liter of water, dried over sodium sulfate, charcoaled and evaporated. The residue is triturated' with hexane and the precipitate is The free base is prepared by dissolving l-(2,6- dichlorophenyl)-l-methylguanidine hydrochloride in 10% sodium hydroxide solution and extracting with ether. The ether is dried and evaporated to dryness to obtain l-(2,6-dichlorophenyl)-l-methylguanidine.

When the N-methylaniline in the above procedures are replaced by the N-loweralkylanilines of this invention-then the corresponding product is obtained.

When the "above procedures are followed using the representative amines of Table I, below, then the corresponding product of Table II, below, is prepared.

TABLE 1 N-methyl-o-chloroaniline N-methyl-m-chloroaniline N-methyI-p-chloroaniline N-methyl-2,3-dichloroaniline N-methyl-2.4dichloroaniline N-methyl2,5-dichloroaniline N-methyl-3,4-dichloroaniline N-methyl-35-dichlorouniline -(o-chlorophenyl l -methylguanidine '(m-chlorophenyU- l -methylguanidine -(p-chlorophenyl l -methylguanidine -(2,3-dichlorophenyl)- l -methylguanidine -(2,4-dichlorophenyl)- l -methylguanidine 2,5-dichlorophenyl)- l -methylguanidine -(3,4-dichlorophenyl)- l -methylguanidine -(3,5-dichlorophenyl)-1-methylguanidine TABLE l-Continued propionylcyanamide benzoylcyanamide phenylcyanamide benzylcyanamide phenethylcyanamide cyclohex-Z-enylcyanamide cyclopropylmethylcyanamide cyclobutylmethylcyanamide cyclopropylethylcyanamide diethylcyanamide methylethylcyanamide methylpropylcyanamide methylcyclopropylcyanamide methylbenzylcyanamide methylacetylcyanamide ethylacetylcyanamide When the anilines of Examples 1 and 2 are condensed with the above cyanamides using the above procedures, then the corresponding products are obtained.

EXAMPLE4 1-(2,6-Dichlorophenyl)-3-acetylguanidine A solution of 5 g (0.024 mole) of 2,6-

dichlorophenylguanidine in 50 ml of tetrahydrofuran is chilled in an ice bath while 2.56 g (0.24 mole) of acetic anhydride is added dropwise. The mixture is. then stirred for 48 hours and then poured into 1 liter of water. The mixture is then stirred for 8 hours and the precipitate is collected to obtain l-(2,6-dichlorophenyl)- 1,3-diacetylguanidine 3 g of this material is stirred at room temperature with ml of conc. hydrochloric acid. The reaction mixture is poured into ice and basicified with cold conc. sodium hydroxide solution. The precipitate is cooled and recrystallized from ethanol: water to obtain 1 (2,6-dichlorophenyl)-3- acetylguanidine.

When acetic anhydride is replaced by propionic an hydride, butyric anhydride, benzoic anhydride, then the products obtained are:

l-(2,6-dichlorophenyl)-3-propionylguanidine 1-(2,6-dichlorophenyl)-3-butyroylguanidine l-(2,6-dichlorophenyl)-3-benzoylguanidine When the above procedures are followed using the anilines of Examples 1 and 2 and the above anhydrides then the corresponding products are obtained.

EXAMPLE 5 l-( p-Fluorophenyl )-3-methylthiourea To a mixture of 55.5 g (0.5 mole) of p-fluoroaniline and 100 ml of xylene is added 36.5 g (0.5 mole) of methylisothiocyanate and the mixture is refluxed for 2 hours. Recrystallization from 1:1 isopropanol/water re sults in l-(p-fluorophenyl)-3-methylthiourea.

When the above procedure is followed using the anilines of Examples 1 and 2 then the corresponding product is obtained.

When methylisothiocyanate is replaced by the iso thiocyanates of Table l, below, then the corresponding products are obtained.

TABLE] ethylisocyanate propylisothiocyanate i-propylisothiocyanate TABLE l-Continued EXAMPLE 6 l-( 2,6-Dichlorophenyl)-3-methylguanidine To 51.8 g (0.68 mole) of ammonium thiocyanatein 300 ml acetone is added 86.8 g (0.62 mole) of benzoyl chloride. The reaction mixture is refluxed for about 5 minutes and then g (0.62 mole) of 2,6-dichloro aniline in 200 ml acetone is added at a rate to maintain reflux. The mixture is refluxed for ly hours, cooled, poured into 1% liter of ice and water, filtered to obtain l-( 2,6-dichlorophenyl )-3-benzoylthiourea.

182.8 g (0.56 mole) of the latter is heated with 1 liter of 10% sodium hydroxide, filtered, acidified while'hot with cone. hydrochloric acid and then made basic with conc. ammonium hydroxide. The mixture is then chilled in an ice both and the resultant 2,6- dichlorophenylthiourea is filtered off. 7

20 g (0.09 mole)'of 2,6Tdichlorphenylthiourea is combined with. 200 ml methanol and 12.9 g (0.09

mole) iodomethane and refluxed for 4 hours. This is then evaporated to dryness and 100 ml hexane is added and the mixture filtered to obtain l-(2,6- dichlorophenyl)-2'methyl-pseudothiouronium iodide.

32.8 g (0.09 mole) of the latter is added to 300 ml of n-butanol. Methyl amine gas is bubbled through this solution while refluxing for 24 hours. The reaction mixture is evaporated to dryness and extracted with 10% sodium hydroxide solution and ether. The ether is washed with 10% sodium hydroxide and then with water, dried and filtered. To this is added ethereal HCl and the precipitate is collected to obtain l-(2,6- dichlorophenyl) 3-methylguanidine hydrochloride.

The free base is prepared by dissolving l-(2,6- dichlorphenyl)-3-methylguanidine hydrochloride in 10% sodium hydroxide solution and extracting with ether. The ether is dried and evaporated to dryness to obtain l-(2,6-dichlorophenyl)-3-methylguanidine.

When the above procedures are followed using the anilines of Examples 1 and 2 then the corresponding products are obtained.

When the above procedures are followed and methylamine is replaced with the amines of Table I, below, then the corresponding products are obtained.

TABLE I TABLE I -Continued cyclobutylmethylamine ethylamine cyclopropylethylamine propylamine 5 dimethylamine i-propylamine diethylamine butylamine methylethylamine pentylamine ethylpropylamine hexylamine' ethylcyclopropylamine heptylamine l0 ethylbenzylamine octylamine dibenzylamine propargylamine N-bcnzylaniline methallylamine azirane 2,4-pentadienylamine azetidine cyclopropylamine 15 piperidine cyclobutylamine homopiperidine cyclopentylamine morpholine cyclohexylamine pyrrolidine aniline v piperazine benzylamine 1 20 Z-methyl-l-azacyclooctane phenethylamine When the above procedures are followed using the anilines of Examples 1 and 2 and the amines of Table I, above, then the corresponding products are obtained.

cyclohex-Z-enylamine cyclopropylmethylamine Starting Materials ,fi-dichloroaniline ethylcyanamide ,6-dichlor0aniline propylcyanimide ,fi-dichloroaniline i-propylcyanamide ,-dichloroaniline butylcyanamide ,fi-dichloroaniline pentylcyanamide ,fi-dichloroaniline hexylcyanamide -dichloroaniline heptylcyanamide -diehloroaniline octylcyanamide -dichloroaniline alkylcyanamide dichloroaniline propargylcyanamide -dichloroaniline methallylcyanamide 2.6-dichlorophenyl) guanidine acetic anhydride 2,6-dichlorophenyl)guanidine propionic anhydride 2,6-dichlorophenyl)guanidine benzoic anhydride 6 6 ,6-dichloroaniline phenethylcyanamide EXAMPLE 7 l Following the procedures of Example 1-6, the following representative compounds may be prepared:

Product l-( 2,6-dichlorophenyl)-3 -methyl-3-ethylguanidine 1-( 2,6-dichlorophenyl)-3-methyl-3-propylguanidine l-( 2,6-dichlorophenyl )-3-methyl-3-cyclopropylguanidine l-( 2,6-dichlorophenyl)-3-methyl-3-benzylguanidine l-( 2,6-dichlorophenyl)-3-methyl-3-acetylguanidine l-( 2,6-dichlorophenyl )-3-ethyl-3-propionylguanidine 2,6-dichlorophenyl)-1,S-dimethylguanidine ,6-dichlorophenyl)- l ,S-diethylguanidine .6-dichlorophenyl)-1-methyl-3-ethylguanidine 2 2 2.6-dichlorophenyl)- l -cthyl-3-methylguanidine 2 l-( 2,6-dichlorophenyl)-l ,3 ,3-trimethylguanidine l( 2.6-dichlorophenyU-3 ,3-octamethyleneguanidine N-(2,6-dichIoropheriylamidino)thiomorpholine l-( 2,6-dichlorophenyl)-3 .3-pentamethyleneguanidine N-(2.6dichlorophcnylamidino)morp holine N -(2,6-dichlorophenylamidino )-N=-methylpiperazine l( 2,6-dichlorophenyl l ,3,3-trimethylguanidine a O\ O Q ow QNNNN m a a O a ouuuwwwAA-hwuwumwuuwuuuuwwu 3,914,306 29 30 3. A compound according to claim 1 where R. R, 6. The compound l-(p-fluorophenyl)-3- and R' are hydrogen. acetylguanidine.

4. The compound l-(2.6-dichlo1 ophenyI)-3- The .c9mpound LWflmmpbenyn'l'methyl-3' acetylguamdme.

acetylguamdmel 8. The compound I-( 2,4,6-trichlorophenyl )-l 5. The compound l-(2,6-dichIorophenyl)-l-methylmethypg,-acety|guanidine 3-acetylguanidine. 

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 where: X is hydrogen, Y is 2-chloro and Z is 6-chloro.
 3. A compound according to claim 1 where R, R'', and R'''''' are hydrogen.
 4. The compound 1-(2,6-dichlorophenyl)-3-acetylguanidine.
 5. The compound 1-(2,6-dichlorophenyl)-1-methyl-3-acetylguanidine.
 6. The compound 1-(p-fluorophenyl)-3-acetylguanidine.
 7. The compound 1-(p-fluorophenyl)-1-methyl-3-acetylguanidine.
 8. The compound 1-(2,4,6-trichlorophenyl)-1-methyl-3-acetylguanidine. 